1. Field of the Invention
The present invention relates to naphthoic acids and derivatives.
2. Description of the Prior Art
Structure-based drug design is a rapidly expanding field that combines synthetic chemistry, enzymology, modeling and crystallography in the targeted development of new drugs. An essential element of structure-based drug design is identification of a lead compound, whether from random screening or from computational procedures, that can be developed into an improved inhibitor through the iterative process of 1) determination of the three-dimensional structure of the complex of the target receptor and lead compound, 2) optimization of inhibitor-receptor interactions through molecular modeling; 3) synthesis of a new inhibitor; and 4) testing of the new inhibitor.
Most drugs are targeted at the active sites of enzymes and other proteins. There are numerous dehydrogenases with critical metabolic roles that represent potential drug targets. The NAD(H) or NADP(H) cofactor binding sites of dehydrogenases have not been widely developed as drug targets, mainly because the structures of cofactor binding sites of dehydrogenases, as determined by x-ray crystallography, are often quite similar, which implies that development of selective dehydrogenase inhibitors will be difficult. There has been some success in developing selective inhibitors that compete for the adenosine part of the cofactor binding site. For example, structure based design of adenosine-related inhibitors of glyceraldehyde-3-P dehydrogenase from trypanosomes has been reported. There has also been some success in developing NAD analogs as potential therapeutics. For example, the anticancer agent tiazofurin (2-.beta.-D-ribofuranosylthiazole-4 carboxamide) is metabolically converted into the NAD analog thiazole-4-carboxamide adenine dinucleotide which is a potent inhibitor of IMP dehydrogenase type 11, the dominant isoenzyme in neoplastic cells. Generally, however, the nicotinamide part of the dinucleotide binding site of dehydrogenases has not been a target in drug design.